The invention generally relates to novel nucleic acids and polypeptides and more particularly to novel nucleic acids encoding polypeptides related to growth factors.
Hepatoma-derived growth factor (HDGF) and HDGF-related proteins (HRP) belong to a gene family with a well-conserved amino acid sequence at the N-terminus. Hepatoma-derived growth factor HDGF was the first member identified in this new family of secreted heparin-binding growth factors that are highly expressed in the fetal aorta. Like other heparin binding proteins, HDGF is an acidic polypeptide with mitogenic activity for fibroblasts
The biologic role of HDGF in vascular growth is unknown. However, HDGF colocalizes with the proliferating cell nuclear antigen (PCNA) in smooth muscles cells in human atherosclerotic carotid arteries, suggesting that HDGF helps regulate smooth muscle growth during development and in response to vascular injury.
The present invention is based, in part, upon the discovery of a nucleic acid encoding a novel polypeptide having homology to hepatoma-derived growth factor (HDGF) protein. The novel hepatoma-derived growth factor X (HDGFX) polynucleotide sequences and the HDGFX polypeptides encoded by these nucleic acid sequences, and fragments, homologs, analogs, and derivatives thereof, are claimed in the invention.
In one aspect, the invention provides an isolated HDGFX nucleic acid (SEQ ID NO:1, as shown in Table 1), that encodes a HDGFX polypeptide, or a fragment, homolog, analog or derivative thereof. The nucleic acid can include, e.g., nucleic acid sequence encoding a polypeptide at least 85% identical to a polypeptide comprising the amino acid sequence of Table 1 (SEQ ID NO:2). The nucleic acid can be, e.g., a genomic DNA fragment, or it can be a cDNA molecule. In another aspect, the invention provides a complement to the HDGFX nucleic acid shown in Table 1, or a fragment, homolog, analog or derivative thereof.
Also included in the invention is a vector containing one or more of the nucleic acids described herein, and a cell containing the vectors or nucleic acids described herein.
The present invention is also directed to host cells transformed with a recombinant expression vector comprising any of the nucleic acid molecules described above.
In one aspect, the invention includes a pharmaceutical composition that includes a HDGFX nucleic acid and a pharmaceutically acceptable carrier or diluent. In a further aspect, the invention includes a substantially purified HDGFX polypeptide, e.g., any of the HDGFX polypeptides encoded by a HDGFX nucleic acid, and fragments, homologs, analogs, and derivatives thereof. The invention also includes a pharmaceutical composition that includes a HDGFX polypeptide and a pharmaceutically acceptable carrier or diluent.
In a further aspect, the invention provides an antibody that binds specifically to a HDGFX polypeptide. The antibody can be, e.g., a monoclonal or polyclonal antibody, and fragments, homologs, analogs, and derivatives thereof. The invention also includes a pharmaceutical composition including HDGFX antibody and a pharmaceutically acceptable carrier or diluent. The present invention is also directed to isolated antibodies that bind to an epitope on a polypeptide encoded by any of the nucleic acid molecules described above.
The present invention is further directed to kits comprising antibodies that bind to a polypeptide encoded by any of the nucleic acid molecules described above and a negative control antibody.
The invention further provides a method for producing a HDGFX polypeptide. The method includes providing a cell containing a HDGFX nucleic acid, e.g., a vector that includes a HDGFX nucleic acid, and culturing the cell under conditions sufficient to express the HDGFX polypeptide encoded by the nucleic acid. The expressed HDGFX polypeptide is then recovered from the cell. Preferably, the cell produces little or no endogenous HDGFX polypeptide. The cell can be, e.g., a prokaryotic cell or eukaryotic cell.
The present invention provides a method of inducing an immune response in a mammal against a polypeptide encoded by any of the nucleic acid molecules disclosed above. In one embodiment, the method includes administering to the mammal an amount of the polypeptide sufficient to induce the immune response. In another embodiment, the method includes administering to the mammal a nucleic acid encoding a HDGFX polypeptide in an amount sufficient to produce enough HDGFX polypeptide to induce the immune response.
The present invention is also directed to methods of identifying a compound that binds to HDGFX polypeptide by contacting the HDGFX polypeptide with a compound and determining whether the compound binds to the HDGFX polypeptide.
The invention further provides methods of identifying a compound that modulates the activity of a HDGFX polypeptide by contacting HDGFX polypeptide with a compound and determining whether the HDGFX polypeptide activity is modified.
The present invention is also directed to compounds that modulate HDGFX polypeptide activity identified by contacting a HDGFX polypeptide with the compound and determining whether the compound modifies activity of the HDGFX polypeptide, binds to the HDGFX polypeptide, or binds to a nucleic acid molecule encoding a HDGFX polypeptide.
In a further aspect, the invention includes a method of diagnosing a tissue proliferation-associated disorder, such as tumors, restenosis, psoriasis, diabetic and post-surgery complications, and rheumatoid arthritis, in a subject. The method includes providing a nucleic acid sample, e.g., RNA or DNA, or both, from the subject and measuring the amount of the HDGFX nucleic acid in the subject nucleic acid sample. The amount of HDGFX nucleic acid sample in the subject nucleic acid is then compared to the amount of HDGFX nucleic acid in a control sample. An alteration in the amount of HDGFX nucleic acid in the sample relative to the amount of HDGFX in the control sample indicates the subject has a tissue proliferation-associated disorder.
In a still further aspect, the invention provides method of treating or preventing or delaying a tissue proliferation-associated disorder. The method includes administering to a subject in which such treatment or prevention or delay is desired a HDGFX nucleic acid, a HDGFX polypeptide, or a HDGFX antibody in an amount sufficient to treat, prevent, or delay a tissue proliferation-associated disorder in the subject.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.